This proposal addresses an important element of the current tuberculosis global epidemic, namely the fact, recently stated in a document released by the NIAID, that we know next to nothing about the newly emerging clinical isolates of M. tuberculosis, many of which are W-Beijing strains. We will test the simple hypothesis here that such strains associated with high rates of transmission are simply more virulent than low transmission strains, with a secondary hypothesis being that the more virulent strains escape acquired immunity by generating regulatory T cells. These simple studies will provide important basic information about the relationship between transmissibility and virulence, and are doable within the context of an R21 application. PUBLIC HEALTH RELEVANCE: As an important NIAID document recently noted, we know almost nothing about the newly emerging clinical strains of tuberculosis, many of which are fall under the W-Beijing family. In this proposed study we will measure the virulence of a panel of Beijing isolates associated with a series of outbreaks in the San Francisco area. We will test the simple hypothesis that strains associated with high transmissibility are of higher virulence in the relevant guinea pig model compared to others that are not readily transmitted.